Amyotrophic Lateral Sclerosis (ALS)

Neurodegenerative diseases

General outline

Jean-Martin Charcot, a French Neurologist, described the ALS in 1874. ALS is a disease of the motor nerve cells in the brain and spinal cord, causing progressive loss of motor control. ALS affects both upper and lower motor neurons throughout the brain and spinal cord.

A-myo-trophic comes from the Greek language. A means no or negative. Myo refers to muscle, and Trophic means nourishment - No muscle nourishment. When a muscle has no nourishment, it atrophies or wastes away. Amyotrophic refers to the muscle atrophy, weakness and fasciculation that signify disease of the lower motor neurons.

Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that nourish the muscles are located. As this area degenerates it leads to scarring or hardening (sclerosis) in the region. Lateral sclerosis refers to the hardness to palpation of the lateral columns of the spinal cord in autopsy specimens, where gliosis follows degeneration of the corticospinal tracts.

Synonyms

Lou Gehrig Disease, Motor Neuron Disease and Charcot disease.

Symptoms and course

In patients with typical ALS, the symptoms are primarily those of weakness, which may start in the hands or legs or be manifested by slurred speech and dysphagia.

On examination there are almost always lower motor neuron signs together with upper motor neuron signs.

Significant bulbar and respiratory weakness soon occurs in about one half of the patients.

Dementia and parkinsonism each occur in less than 5% of patients. Dementia often antedates motor involvement. Cognitive dysfunctions are apathy, poor attention, poor motivation, altered social skills and behaviour abnormalities.

Familial cases are inherited as a dominant trait with variable penetrance and expressivities.

The rate at which ALS progresses can be quite variable from one person to another. Although the mean survival time with ALS is three to five years, many people live five, ten or more years. In a small number of people, ALS is known to remit or halt its progression, though there is no scientific understanding as to how and why this happens.

Caregiver problems

A multidiciplinar care is necessary in ASL. Discussion of the diagnosis by sympathetic personnel may reduce anxiety in patients and relatives. Regular reviews by home health staff for family and psychosocial problems, crisis situations and the need for equipment or community services is vital.

Active management of patients by trained physical, occupational, and speech therapists is helpful.

Causes and risk factors

The aetiology is likely multifactorial involving both genetic and environmental factors.

Genetic factors

Familial clustering of ALS has been recognised for many years and pedigrees of autosomal dominant inheritance of up to six generations recorded.

The incidence of individuals with ALS with another affected family member has been reported as around 5 to 10% in several studies. In some of these families, there is clear evidence of autosomal dominant inheritance and rarely of autosomal recessive inheritance. Many families may contain only two affected individuals in the same generation or more distantly related, and it is not possible immediately to say whether these reflect common genetic or environmental influences.

In 1993,Rosen et al. described mutations in gene encoding superoxide dismutase 1 (SOD1). These mutations account for 20 percent of cases of familial ALS. The remaining 80 percent are caused by mutations in other genes. Five percent of people with apparently sporadic ALS also have SOD1 mutations. More than 90 SOD1 mutations involve 40 of the 153 amino acid residues. All SOD1 mutations are dominant, except for the substitution of alanine for aspartate at position 90 (D90A), which can be either recessive or dominant.

Environmental factors

Exposure to heavy metals

Viral Infection and Prion Disease as Causes

Autoimmunity

Genetics

Familial clustering of ALS has been recognised for many years and pedigrees of autosomal dominant inheritance of up to six generations recorded.

The incidence of individuals with ALS with another affected family member has been reported as around 5 to 10% in several studies. In some of these families, there is clear evidence of autosomal dominant inheritance and rarely of autosomal recessive inheritance. Many families may contain only two affected individuals in the same generation or more distantly related, and it is not possible immediately to say whether these reflect common genetic or environmental influences.

In 1993,Rosen et al. described mutations in gene encoding superoxide dismutase 1 (SOD1). These mutations account for 20 percent of cases of familial ALS. The remaining 80 percent are caused by mutations in other genes. Five percent of people with apparently sporadic ALS also have SOD1 mutations. More than 90 SOD1 mutations involve 40 of the 153 amino acid residues. All SOD1 mutations are dominant, except for the substitution of alanine for aspartate at position 90 (D90A), which can be either recessive or dominant.

Frequency

The worldwide annual incidence rates for classical ALS range between 0.4 and 1.8 per 100 000 population, and the prevalence rates between 4 and 6 per 100 000 population.

Several studies have shown an increasing incidence of ALS in individuals older than 60. The annual range of death is about 1 per 100 000.

The incidence and prevalence of ALS vary little worldwide, with notable pockets of higher prevalence, especially in Guam. During World War II, neuropathologist Harry Zimmerman noted an unusual frequency of ALS, parkinsonism and dementia in Guam.

Epidemiologic studies indicated that the prevalence of ALS in Guam was 50 times the prevalence anywhere else. Both the parkinsonism–dementia–ALS complex and ALS alone remain prevalent in Guam.

The cause of Guamanian ALS with parkinsonism and dementia is unknown. Heredity was discounted because the spouses of many patients were also affected, and no environmental causes or virus were found.

Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. However, cases of the disease do occur in persons in their twenties and thirties. Generally though, ALS occurs in greater percentages as men and women grow older. ALS is 20% more common in men than in women. However with increasing age, the incidence of ALS is more equal between men and women. Half of all people affected with ALS live at least three or more years after diagnosis. Twenty percent live five years or more; up to ten percent will survive more than ten years.

Diagnostic procedures

The clinical diagnosis of ALS is probably correct in more than 95 percent of cases.

Electromyographic demonstration of denervation in at least three limbs confirms the findings of lower motor neuron abnormalities. Two methods are being used to document the involvement of upper neurons:

Magnetic resonance spectroscopy measures the number of surviving neurons in the motor cortex

Magnetic stimulation of the motor cortex assesses conduction in the corticospinal tracts. The sensitivity and specificity of the two approaches seem to be equal and need to be improved. Magnetic resonance imaging may show high signal intensity in the corticospinal tracts.

Care and treatment

Riluzole, a glutamate antagonist, is the only drug approved by the Food and Drug Administration for the treatment of ALS. In two therapeutic trials, riluzole prolonged survival by three to six months.

In one of these trials, treatment slightly slowed the decline in the strength of limb muscle; there was no benefit with respect to many measures of function in either trial. In one retrospective analysis, patients who received riluzole remained in a milder stage of disease longer than did controls. For patients, the effects are invisible.

Ongoing research/Clinical trials

Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease.

Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficiency.

Acknowledgements

This information was gathered in the framework of the European Commission financed project "Rare forms of dementia". Neither the European Commission nor any person acting on its behalf is responsible for any use that might be made of the following information.